Gene Regulation Networks Group

Gene Regulation Networks Group

Because they have many targets, microRNAs are ideally suited to act as network regulators via their simultaneous targeting of multiple components within a signalling pathway. Utilising cutting-edge methodologies and mass sequencing techniques, we are investigating how microRNAs select and regulate their target genes and how these genes interact to regulate the invasive capacity of cancer cells. We are also investigating new or poorly understood roles for microRNAs in cancer, including the impact of naturally occurring microRNA sequence variants and the potential for microRNAs to directly regulate transcription within the nucleus, a mechanism for which there is good evidence but little recognition. We aim to publish high impact papers of direct relevance to microRNA function in the context of human cancer.

Potential student research projects

Possible student research projects include both wet-bench and/or bioinformatic projects. Research project areas include:

The role of naturally occurring microRNA variants (isomiRs):

MicroRNAs are expressed as a series of naturally-occurring sequence variants called isomiRs. We are investigating examples of isomiRs whereby these subtle variations in sequence can have profound effects on microRNA function.

The role of nuclear microRNAs:

In addition to their well characterised role in the cytoplasm, a significant amount of microRNA also exists in the nucleus. Recent findings suggest this may have a role directly regulating transcription through binding target gene promoters and either recruiting or inhibiting RNA polymerase. We are investigating this new and largely unrecognized mechanism of microRNA function, especially with regard to microRNAs with known roles in the initiation or progression of cancer.

MicroRNA-regulated networks:

Genes function within wider genetic networks which microRNAs are ideally suited to regulate at multiple levels to achieve stronger or more selective functions. We are investigating signalling networks of genes regulated by microRNAs relevant to cancer, such as the multi-level regulation of EGF signalling that is over-active in cancer where it regulates cancer survival, proliferation and migration.

Recent publications

Bracken CP, Scott HS, Goodall GJ. A network-biology perspective of microRNA function and dysfunction in cancerd. Nature Reviews Genetics, 2016 (in press)

Bracken CP, Khew-Goodall Y, Goodall GJ. Network-based approaches to understand the roles of miR-200 and other microRNAs in Cancer. Cancer Research, 2015, 75(13):2594-9.

Yu F, Bracken CP, Pillman KA, Lawrence DM, Goodall GJ, Callen DF, Neilsen PM. p53 Represses the Oncogenic Sno-MiR-28 Derived from a SnoRNA. PLoS One, 2015, 10(6):e0129190.

Cursons J, Leuchowius KJ, Waltham M, Tomaskovic-Crook E, Foroutan M, Bracken CP, Redfern A, Crampin EJ, Street I, Davis MJ, Thompson EW. Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines. Cell Communication and Signalling, 2015, 13:26. doi: 10.1186/s12964-015-0106-x.

Thomson DW, Pillman KA, Anderson ML, Lawrence DM, Toubia J, Goodall GJ, Bracken CP. Assessing the gene regulatory properties of Argonaute-bound small RNAs of diverse genomic origin. Nucleic Acids Research, 2015, 43(1):470-81

Bracken CP, Li X, Wright JA, Lawrence DM, Pillman KA, Salmanidis M, Anderson MA, Dredge BK, Gregory PA, Tsykin A, Neilsen C, Thomson DW, Bert AG, Leerberg JM, Yap AS, Jensen KB, Khew-Goodall Y, Goodall GJ. Genome-wide identification of miR-200 targets reveals a regulatory network controlling cell invasion. EMBO Journal, 2014, 33(18):2040-56.

Salmanidis M, Pillman KA, Goodall GJ, Bracken CP. Direct transcriptional regulation by nuclear microRNAs. International Journal of Biochemistry and Cell Biology, 2014, 54:304-11.

Li X, Roslan S, Johnstone CN, Wright JA, Bracken CP, Anderson M, Bert AG, Selth LA, Anderson RL, Goodall GJ, Gregory PA, Khew-Goodall Y. MiR-200 can repress breast cancer metastasis through ZEB1-independent but moesin-dependent pathways. Oncogene, 2014, 33(31):4077-88.

Thomson DW, Bracken CP, Szubert JM, Goodall GJ. On measuring miRNAs after transient transfection of mimics or antisense inhibitors. PLoS One. 2013, 8(1):e55214.

Neilsen C, Goodall GJ and Bracken CP. IsomiRs - the overlooked repertoire in the dynamic microRNAome. Trends in Genetics, 2012, 28(11):544.

Neilsen PM, Noll JE, Mattiske S, Bracken CP, Gregory PA, Schul RG, Lim SG, Kumar R, Suetani RJ, Goodall GJ and Callen DF. Mutant p53 drives invasion in breast tumors through up-regulation of miR-155. Oncogene, 32(24):2992-3000.

Mercer TR, Neph S, Dinger ME, Crawford J, Smith MA, Shearwood AJ, Rackham O, Haugen E, Bracken CP, Stamatoyannopoulos JA, Filopovska A, Mattick JS. The human mitochondrial transcriptome. Cell, 2011, 136(4):645-658.

Thomson DW, Bracken CP, Goodall GJ. Experimental strategies for microRNA target identification. Nucleic Acids Research, 2011, 39(16):6845-6853.

Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, Morris M, Wyatt L, Farshid G, Lindeman GJ, Shannon MF, Drew PA, Khew-Goodall Y, Goodall GJ. A miR-200 / ZEB / TGF-b signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Molecular Biology of the Cell, 2011, 22(10):1686-1698.

Bracken CP, Szubert JM, Mercer TR, Dinger ME, Thomson DW, Mattick JS, Michael MZ, Goodall GJ. Global analysis of the mammalian RNA degradome reveals widespread miRNA-dependent and miRNA independent endonucleolytic cleavage. Nucleic Acids Research, 2011, 39(13):5658-5668.

Mercer TR, Dinger ME, Bracken CP, Kolle G, Szubert JM, Korbie DJ, Askarian-Amiri ME, Gardiner BB, Goodall GJ, Grimmond SM, Mattick JS. Regulated post-transcriptional RNA cleavage diversifies the eukaryotic transcriptome. Genome Research, 2010, 20(12):1639-50.

Bracken CP, Gregory PA, Khew-Goodall Y, Goodall GJ. The role of microRNAs in metastasis and epithelial-mesenchymal transition. Cellular and Molecular Life Science, 2009, 66(10):1682-99.

Gregory PA, Bracken CP, Bert AG, Goodall GJ. MicroRNAs as regulators of epithelial-mesenchymal transition. Cell Cycle, 2008, 7(20):3112-8

Bracken CP, Gregory PA, Kolenikoff N, Bert A, Frances-Shannon M and Goodall G. A double-negative feedback loop between ZEB1-SIP1 and the miR-200 family controls epithelial-mesenchymal transition. Cancer Research, 2008, 68(19):7846-54.